ArticleNeoplasia (New York, N.Y.)2011
DNA-PK mediates AKT activation and apoptosis inhibition in clinically acquired platinum resistance.
Article in Neoplasia (New York, N.Y.), 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 82 papers.
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Who cites it
82 citing papers in PubMed, 138 citations in OpenAlex.
- Targeting NHEJ activates STING signaling through MYC degradation to boost antitumor immunity in SCLC.Nature communications · 2026Article
- Signaling networks and MiRNA crosstalk in ovarian cancer chemoresistance.Journal of ovarian research · 2025Review
- The lncRNA TPTEP1 suppresses PI3K/AKT signalling and inhibits ovarian cancer progression by interacting with PTBP1.Journal of cellular and molecular medicine · 2024Article
- Deciphering the ghost proteome in ovarian cancer cells by deep proteogenomic characterization.Cell death & disease · 2024Article
- S6K1 Controls DNA Damage Signaling Modulated by the MRN Complex to Induce Radioresistance in Lung Cancer.International journal of molecular sciences · 2024Article
- The impact of pathogenicSAGE open medicine · 2024Article
- AMIGO2 attenuates innate cisplatin sensitivity by suppression of GSDME-conferred pyroptosis in non-small cell lung cancer.Journal of cellular and molecular medicine · 2023Article
- DNA Damage Response Alterations in Ovarian Cancer: From Molecular Mechanisms to Therapeutic Opportunities.Cancers · 2023Review
- Mucin 4 Confers Gemcitabine Resistance and an Unfavorable Prognosis in Patients with Cholangiocarcinoma via AKT Activation.International journal of biological sciences · 2023Article
- eIF3a regulation of mTOR signaling and translational control via HuR in cellular response to DNA damage.Oncogene · 2022Article
- DNA repair protein DNA-PK protects PC12 cells from oxidative stress-induced apoptosis involving AKT phosphorylation.Molecular biology reports · 2022Article
- DNA-PK promotes activation of the survival kinase AKT in response to DNA damage through an mTORC2-ECT2 pathway.Science signaling · 2022Article
- Complex molecular profile of DNA repair genes in epithelial ovarian carcinoma patients with different sensitivity to platinum-based therapy.Frontiers in oncology · 2022Article
- Radioresistance in rhabdomyosarcomas: Much more than a question of dose.Frontiers in oncology · 2022Review
- TTK is a potential therapeutic target for cisplatin-resistant ovarian cancer.Journal of ovarian research · 2021Article
- Integrating Cancer Vaccines in the Standard-of-Care of Ovarian Cancer: Translating Preclinical Models to Human.Cancers · 2021Review
- Proteomics-derived basal biomarker DNA-PKcs is associated with intrinsic subtype and long-term clinical outcomes in breast cancer.NPJ breast cancer · 2021Article
- The component of the mJournal of experimental & clinical cancer research : CR · 2021Article
- Targeting DNA Damage Response and Repair to Enhance Therapeutic Index in Cisplatin-Based Cancer Treatment.International journal of molecular sciences · 2021Review
- Induction of APOBEC3B expression by chemotherapy drugs is mediated by DNA-PK-directed activation of NF-κB.Oncogene · 2021Article
22 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
Clinical resistance to chemotherapy is a frequent event in cancer treatment and is closely linked to poor outcome. High-grade serous (HGS) ovarian cancer is characterized by p53 mutation and high levels of genomic instability. Treatment includes platinum-based chemotherapy and initial response rates are high; however, resistance is frequently acquired, at which point treatment options are largely palliative. Recent data indicate that platinum-resistant clones exist within the sensitive primary tumor at presentation, implying resistant cell selection after treatment with platinum chemotherapy. The AKT pathway is central to cell survival and has been implicated in platinum resistance. Here, we show that platinum exposure induces an AKT-dependent, prosurvival, DNA damage response in clinically platinum-resistant but not platinum-sensitive cells. AKT relocates to the nucleus of resistant cells where it is phosphorylated specifically on S473 by DNA-dependent protein kinase (DNA-PK), and this activation inhibits cisplatin-mediated apoptosis. Inhibition of DNA-PK or AKT, but not mTORC2, restores platinum sensitivity in a panel of clinically resistant HGS ovarian cancer cell lines: we also demonstrate these effects in other tumor types. Resensitization is associated with prevention of AKT-mediated BAD phosphorylation. Strikingly, in patient-matched sensitive cells, we do not see enhanced apoptosis on combining cisplatin with AKT or DNA-PK inhibition. Insulin-mediated activation of AKT is unaffected by DNA-PK inhibitor treatment, suggesting that this effect is restricted to DNA damage-mediated activation of AKT and that, clinically, DNA-PK inhibition might prevent platinum-induced AKT activation without interfering with normal glucose homeostasis, an unwanted toxicity of direct AKT inhibitors.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.